[Federal Register Volume 77, Number 44 (Tuesday, March 6, 2012)]
[Notices]
[Pages 13339-13343]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-5302]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-N-0169]


Report on the Performance of Drug and Biologics Firms in 
Conducting Postmarketing Requirements and Commitments; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: Under the Food and Drug Administration Modernization Act of 
1997 (Modernization Act), the Food and Drug Administration (FDA) is 
required to report annually in the Federal Register on the status of 
postmarketing requirements and commitments required of, or agreed upon 
by, holders of approved drug and biological products. This notice is 
the Agency's report on the status of the studies and clinical trials 
that applicants have agreed to, or are required to, conduct.

FOR FURTHER INFORMATION CONTACT: Meg Pease-Fye, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 4156, Silver Spring, MD 20993-0002, 301-
796-0700; or Stephen Ripley, Center for Biologics Evaluation and 
Research (HFM-17), Food and Drug Administration, 1401 Rockville Pike, 
suite 200N, Rockville, MD 20852, 301-827-6210.

SUPPLEMENTARY INFORMATION: 

I. Background

A. The Modernization Act

    Section 130(a) of the Modernization Act (Pub. L. 105-115) amended 
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) by adding a new 
provision requiring reports of certain postmarketing studies, including 
clinical trials, for human drug and biological products (section 506B 
of the FD&C Act (21 U.S.C. 356b)). Section 506B of the FD&C Act 
provides FDA with additional authority to monitor the progress of a 
postmarketing study or clinical trial that an applicant has been 
required to, or has agreed to, conduct by requiring the applicant to 
submit a report annually providing information on the status of the 
postmarketing study/clinical trial. This report must also include 
reasons, if any, for failure to complete the study/clinical trial. 
These studies and clinical trials are intended to further define the 
safety, efficacy, or optimal use of a product, and therefore play a 
vital role in fully characterizing the product.
    Under the Modernization Act, commitments to conduct postmarketing 
studies or clinical trials included both studies/clinical trials that 
applicants agreed to conduct, as well as studies/clinical trials that 
applicants were required to conduct under FDA regulations.\1\
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    \1\ Before passage of the Food and Drug Administration 
Amendments Act of 2007 (FDAAA), FDA could require postmarketing 
studies and clinical trials under the following circumstances: To 
verify adn describe clinical benefit for a human drug approved in 
accordance with the accelerated approval provisions in section 
506(b)(2)(A) of the FD&C Act (21 CFR 314.510 and 601.41); for a drug 
approved on the basis of animal efficacy data because human efficacy 
trials are not ethical or feasible (21 CFR 314.610(b)(1) and 
601.91(b)(1)): and for marketed drugs that not adequately labeled 
for children under section 505B of the FD&C Act (Pediatric Research 
Equity Act (21 U.S.C. 355c; Pub. L. 108-155)).
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B. The Food and Drug Administration Amendments Act of 2007

    On September 27, 2007, the President signed Public Law 110-85, the 
Food and Drug Administration Amendments Act of 2007 (FDAAA). Section 
901, in Title IX of FDAAA, created a new section 505(o) of the FD&C Act 
authorizing FDA to require certain studies and clinical trials for 
human drug and biological products approved under section 505 of the 
FD&C Act or section 351 of the Public Health Service Act. Under FDAAA, 
FDA has been given additional authority to require applicants to 
conduct and report on postmarketing studies and clinical trials to 
assess a known serious risk, assess signals of serious risk, or 
identify an unexpected serious risk related to the use of a product. 
This new authority became effective on March 25, 2008. FDA may now take 
enforcement action against applicants who fail to conduct studies and 
clinical trials required under FDAAA, as well as studies and clinical 
trials required under FDA regulations (see sections 505(o)(1), 502(z), 
and 303(f)(4) of the FD&C Act (21 U.S.C. 355(o)(1), 352(z), and 
333(f)(4))).
    Although regulations implementing the Modernization Act 
postmarketing authorities use the term ``postmarketing commitment'' to 
refer to both required

[[Page 13340]]

studies and studies applicants agree to conduct, in light of the new 
authorities enacted in FDAAA, FDA has decided it is important to 
distinguish between enforceable postmarketing requirements and 
unenforceable postmarketing commitments. Therefore, in this notice and 
report, FDA refers to studies/clinical trials that an applicant is 
required to conduct as ``postmarketing requirements'' (PMRs) and 
studies/clinical trials that an applicant agrees to but is not required 
to conduct as ``postmarketing commitments'' (PMCs). Both are addressed 
in this notice and report.

C. FDA's Implementing Regulations

    On October 30, 2000 (65 FR 64607), FDA published a final rule 
implementing section 130 of the Modernization Act. This rule modified 
the annual report requirements for new drug applications (NDAs) and 
abbreviated new drug applications (ANDAs) by revising Sec.  
314.81(b)(2)(vii) (21 CFR 314.81(b)(2)(vii)). The rule also created a 
new annual reporting requirement for biologics license applications 
(BLAs) by establishing Sec.  601.70 (21 CFR 601.70). The rule described 
the content and format of the annual progress report, and clarified the 
scope of the reporting requirement and the timing for submission of the 
annual progress reports. The rule became effective on April 30, 2001. 
The regulations apply only to human drug and biological products 
approved under NDAs, ANDAs, and BLAs. They do not apply to animal drugs 
or to biological products regulated under the medical device 
authorities.
    The reporting requirements under Sec. Sec.  314.81(b)(2)(vii) and 
601.70 apply to PMRs and PMCs made on or before the enactment of the 
Modernization Act (November 21, 1997), as well as those made after that 
date. Therefore, studies and clinical trials required under FDAAA are 
covered by the reporting requirements in these regulations.
    Sections 314.81(b)(2)(vii) and 601.70 require applicants of 
approved drug and biological products to submit annually a report on 
the status of each clinical safety, clinical efficacy, clinical 
pharmacology, and nonclinical toxicology study/clinical trial either 
required by FDA or that they have committed to conduct, either at the 
time of approval or after approval of their NDA, ANDA, or BLA. The 
status of PMCs concerning chemistry, manufacturing, and production 
controls and the status of other studies/clinical trials conducted on 
an applicant's own initiative are not required to be reported under 
Sec. Sec.  314.81(b)(2)(vii) and 601.70 and are not addressed in this 
report. It should be noted, however, that applicants are required to 
report to FDA on these commitments made for NDAs and ANDAs under Sec.  
314.81(b)(2)(viii). Furthermore, section 505(o)(3)(E) of the FD&C Act, 
as amended by FDAAA, requires that applicants report periodically on 
the status of each required study/clinical trial and each study/
clinical trial ``otherwise undertaken * * * to investigate a safety 
issue * * *.''
    According to the regulations, once a PMR has been required, or a 
PMC has been agreed upon, an applicant must report on the progress of 
the PMR/PMC on the anniversary of the product's approval until the PMR/
PMC is completed or terminated and FDA determines that the PMR/PMC has 
been fulfilled or that the PMR/PMC is either no longer feasible or 
would no longer provide useful information. The annual progress report 
must include a description of the PMR/PMC, a schedule for completing 
the PMR/PMC, and a characterization of the current status of the PMR/
PMC. The report must also provide an explanation of the PMR/PMC status 
by describing briefly the progress of the PMR/PMC. A PMR/PMC schedule 
is expected to include the actual or projected dates for the following: 
(1) Submission of the final protocol to FDA, (2) completion of the 
study/clinical trial, and (3) submission of the final report to FDA. 
The status of the PMR/PMC must be described in the annual report 
according to the following definitions:
     Pending: The study/clinical trial has not been initiated 
(i.e., no subjects have been enrolled or animals dosed), but does not 
meet the criteria for delayed (i.e., the original projected date for 
initiation of subject accrual or initiation of animal dosing has not 
passed);
     Ongoing: The study/clinical trial is proceeding according 
to or ahead of the original schedule;
     Delayed: The study/clinical trial is behind the original 
schedule;
     Terminated: The study/clinical trial was ended before 
completion, but a final report has not been submitted to FDA; or
     Submitted: The study/clinical trial has been completed or 
terminated, and a final report has been submitted to FDA.
    Databases containing information on PMRs/PMCs are maintained at the 
Center for Drug Evaluation and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER).

II. Summary of Information From Postmarketing Status Reports

    This report, published to fulfill the annual reporting requirement 
under the Modernization Act, summarizes the status of PMRs and PMCs as 
of September 30, 2011. If a requirement or commitment did not have a 
schedule, or a postmarketing progress report was not received in the 
previous 12 months, the PMR/PMC is categorized according to the most 
recent information available to the Agency.\2\
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    \2\ Although the data included in this report do not include a 
summary of reports that applicants have failed to file by their due 
date, the Agency notes that it may take appropriate regulatory 
action in the event reports are not filed on a timely basis.
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    Information in this report covers any PMR/PMC that was made, in 
writing, at the time of approval or after approval of an application or 
a supplement to an application, including PMRs required under FDAAA 
(section 505(o)(3) of the FD&C Act), PMRs required under FDA 
regulations (e.g., PMRs required to demonstrate clinical benefit of a 
product following accelerated approval (see footnote 1 of this 
document)), and PMCs agreed to by the applicant.
    Information summarized in this report includes the following: (1) 
The number of applicants with open (uncompleted) PMRs/PMCs, (2) the 
number of open PMRs/PMCs, (3) the status of open PMRs/PMCs as reported 
in Sec.  314.81(b)(2)(vii) or Sec.  601.70 annual reports, (4) the 
status of concluded PMRs/PMCs as determined by FDA, and (5) the number 
of applications with open PMRs/PMCs for which applicants did not submit 
an annual report within 60 days of the anniversary date of U.S. 
approval.
    Additional information about PMRs/PMCs submitted by applicants to 
CDER and CBER is provided on FDA's Web site at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm.'' Neither the Web site nor 
this notice include information about PMCs concerning chemistry, 
manufacturing, and controls. It is FDA policy not to post information 
on the Web site until it has been reviewed for accuracy. Numbers 
published in this notice cannot be compared with the numbers resulting 
from searches of the Web site because this notice incorporates totals 
for all PMRs/PMCs in FDA databases, including PMRs/PMCs undergoing 
review for accuracy. In addition, the report in this notice will be 
updated annually while the Web site is updated quarterly (i.e., in 
January, April, July, and October).

[[Page 13341]]

    Many applicants have more than one approved product and for many 
products there is more than one PMR or PMC. Specifically, there were 
175 unique applicants with 198 NDAs/ANDAs that had open PMRs/PMCs. 
There were 72 unique applicants with 99 BLAs that had open PMRs/PMCs.
    Annual status reports are required to be submitted for each open 
PMR/PMC within 60 days of the anniversary date of U.S. approval of the 
original application. In fiscal year 2011 (FY11), 21 percent (43/208) 
of NDA/ANDA and 41 percent (41/99) of BLA annual status reports were 
not submitted within 60 days of the anniversary date of U.S. approval 
of the original application. Of the annual status reports due but not 
submitted on time, 100 percent of the NDA/ANDA and 56 percent (23/41) 
of the BLA reports were submitted before the close of FY11 (September 
30, 2011).
    Most PMRs are progressing on schedule (87 percent for NDAs/ANDAs; 
88 percent for BLAs). Most PMCs are also progressing on schedule (80 
percent for NDAs/ANDAs; 75 percent for BLAs). Most of the PMCs that are 
currently listed in the database were developed before the 
postmarketing requirements section of FDAAA took effect.\3\
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    \3\ There are existing PMCs established before FDAAA that might 
meet current FDAAA standards for required safety studies/clinical 
trials under section 505(o)(3)(B) of the FD&C Act. Under section 
505(o)(3)(c) of the FD&C Act, the Agency may convert pre-existing 
PMCs into PMRs if it becomes aware of new safety information.
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III. About This Report

    This report provides six separate summary tables. The tables in 
this document distinguish between PMRs and PMCs and between on-schedule 
and off-schedule PMRs and PMCs according to the original schedule 
milestones. On-schedule PMRs/PMCs are categorized as pending, ongoing, 
or submitted. Off-schedule PMRs/PMCs that have missed one of the 
original milestone dates are categorized as delayed or terminated. The 
tables include data as of September 30, 2011.
    Table 1 of this document provides an overall summary of the data on 
all PMRs and PMCs. Tables 2 and 3 of this document provide detail on 
PMRs. Table 2 of this document provides additional detail on the status 
of on-schedule PMRs.
    Table 1 of this document shows that most PMRs (87 percent for NDAs/
ANDAs and 88 percent for BLAs) and most PMCs (80 percent for NDAs/ANDAs 
and 75 percent for BLAs) are on schedule. Overall, of the PMRs that are 
pending (i.e. , have not been initiated), 92 percent were created 
within the past 3 years. Table 2 of this document shows that 49 percent 
of pending PMRs for drug and biological products are in response to the 
Pediatric Research and Equity Act (PREA), under which FDA requires 
sponsors to study new drugs, when appropriate, for pediatric 
populations. Under section 505B(a)(3) of the FD&C Act, the initiation 
of these studies generally is deferred until required safety 
information from other studies has first been submitted and reviewed. 
PMRs for products approved under the animal efficacy rule (21 CFR 
314.600 for drugs; 21 CFR 601.90 for biological products) can be 
conducted only when the product is used for its indication as a 
counterterrorism measure. In the absence of a public health emergency, 
these studies/clinical trials will remain pending indefinitely. The 
next largest category of pending PMRs for drug and biological products 
(49 percent) comprises those studies/clinical trials required by FDA 
under FDAAA, which became effective on March 25, 2008.
    Table 3 of this document provides additional detail on the status 
of off-schedule PMRs. The majority of off-schedule PMRs (which account 
for 13 percent of the total for NDAs/ANDAs and 12 percent for BLAs) are 
delayed according to the original schedule milestones (98 percent (83/
85) for NDAs/ANDAs; 95 percent (20/21) for BLAs). In certain 
situations, the original schedules may have been adjusted for 
unanticipated delays in the progress of the study/clinical trial (e.g. 
, difficulties with subject enrollment in a trial for a marketed drug 
or need for additional time to analyze results). In this report, study/
clinical trial status reflects the status in relation to the original 
study/clinical trial schedule regardless of whether FDA has 
acknowledged that additional time may be required to complete the 
study/clinical trial.
    Tables 4 and 5 of this document provide additional detail on the 
status of PMCs. Table 4 of this document provides additional detail on 
the status of on-schedule PMCs. Pending PMCs comprise 48 percent (141/
295) of the on-schedule NDA/ANDA PMCs and 39 percent (81/209) of the 
on-schedule BLA PMCs.
    Table 5 of this document provides additional details on the status 
of off-schedule PMCs. The majority of off-schedule PMCs (which account 
for 20 percent for NDAs/ANDAs and 25 percent for BLAs) are delayed 
according to the original schedule milestones (93 percent (69/74) for 
NDAs/ANDAs; 97 percent (69/71) for BLAs). As noted previously in this 
document, this report reflects the original due dates for study/
clinical trial results and does not reflect discussions between the 
Agency and the sponsor regarding studies/clinical trials that may 
require more time for completion.
    Table 6 of this document provides details about PMRs and PMCs that 
were concluded in the previous year. The majority of concluded PMRs and 
PMCs were fulfilled (70 percent of NDA/ANDA PMRs and 84 percent of BLA 
PMRs; 85 percent of NDA/ANDA PMCs and 80 percent of BLA PMCs).

     Table 1--Summary of Postmarketing Requirements and Commitments
                   [Numbers as of September 30, 2011]
------------------------------------------------------------------------
                                             NDA/ANDA
                                            (percent of    BLA (percent
                                           total PMR or    of total PMR
                                            percent of     or percent of
                                            total PMC)    total PMC) \1\
------------------------------------------------------------------------
Number of open PMRs.....................            675             176
    On-schedule open PMRs (see table 2         590 (87%)       155 (88%)
     of this document)..................
    Off-schedule open PMRs (see table 3         85 (13%)        21 (12%)
     of this document)..................
Number of open PMCs.....................            369             280
    On-schedule open PMCs (see table 4         295 (80%)       209 (75%)
     of this document)..................

[[Page 13342]]

 
    Off-schedule open PMCs (see table 5         74 (20%)        71 (25%)
     of this document)..................
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\1\ On October 1, 2003, FDA completed a consolidation of certain
  therapeutic products formerly regulated by CBER into CDER.
  Consequently, CDER now reviews many BLAs. Fiscal year statistics for
  postmarketing requirements and commitments for BLAs reviewed by CDER
  are included in BLA totals in this table.


       Table 2--Summary of On-Schedule Postmarketing Requirements
                   [Numbers as of September 30, 2011]
------------------------------------------------------------------------
                                             NDA/ANDA      BLA (percent
          On-Schedule open PMRs             (percent of    of total PMR)
                                            Total PMR)          \1\
------------------------------------------------------------------------
Pending (by type):
    Accelerated approval................              8               1
    PREA \2\............................            238              34
    Animal efficacy \3\.................              1               0
    FDAAA safety (since March 25, 2008).            199              72
                                         -------------------------------
        Total...........................       446 (66%)       107 (61%)
Ongoing:
    Accelerated approval................             13               9
    PREA \2\............................             35               5
    Animal efficacy \3\.................              0               0
    FDAAA safety (since March 25, 2008).             41              23
                                         -------------------------------
        Total...........................        89 (13%)        37 (21%)
Submitted:
    Accelerated approval................              3               2
    PREA \2\............................             24               4
    Animal efficacy \3\.................              0               0
    FDAAA safety (since March 25, 2008).             28               5
                                         -------------------------------
        Total...........................         55 (8%)         11 (6%)
                                         -------------------------------
            Combined total..............       590 (87%)       155 (88%)
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.
\2\ Many PREA studies have a pending status. PREA studies are usually
  deferred because the product is ready for approval in adults.
  Initiation of these studies also may be deferred until additional
  safety information from other studies has first been submitted and
  reviewed.
\3\ PMRs for products approved under the animal efficacy rule (21 CFR
  314.600 for drugs; 21 CFR 601.90 for biological products) can be
  conducted only when the product is used for its indication as a
  counterterrorism measure. In the absence of a public health emergency,
  these studies/clinical trials will remain pending indefinitely.


       Table 3--Summary of Off-Schedule Postmarketing Requirements
                   [Numbers as of September 30, 2011]
------------------------------------------------------------------------
                                             NDA/ANDA      BLA (percent
         Off-Schedule open PMRs             (percent of    of total PMR)
                                            total PMR)          \1\
------------------------------------------------------------------------
Delayed:
    Accelerated approval................               5               2
    PREA................................              64              12
    Animal efficacy.....................               1               0
    FDAAA safety (since March 25, 2008).              13               6
                                         -------------------------------
        Total...........................        83 (12%)        20 (11%)
Terminated..............................        2 (0.3%)        1 (0.6%)
                                         -------------------------------
        Combined total..................        85 (13%)        21 (12%)
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.


[[Page 13343]]


        Table 4--Summary of On-Schedule Postmarketing Commitments
                   [Numbers as of September 30, 2011]
------------------------------------------------------------------------
                                             NDA/ANDA      BLA (percent
          On-Schedule open PMCs             (percent of    of total PMC)
                                            total PMC)          \1\
------------------------------------------------------------------------
Pending.................................       141 (38%)        81 (29%)
Ongoing.................................        77 (21%)        72 (26%)
Submitted...............................        77 (21%)        56 (20%)
                                         -------------------------------
    Combined total......................       295 (80%)       209 (75%)
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.


       Table 5--Summary of Off-Schedule Postmarketing Commitments
                   [Numbers as of September 30, 2011]
------------------------------------------------------------------------
                                             NDA/ANDA      BLA (percent
         Off-Schedule open PMCs             (percent of    of total PMC)
                                            total PMC)          \1\
------------------------------------------------------------------------
Delayed.................................        69 (19%)        69 (25%)
Terminated..............................          5 (1%)        2 (0.7%)
                                         -------------------------------
    Combined total......................        74 (20%)        71 (25%)
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.


Table 6--Summary of Concluded Postmarketing Requirements and Commitments
                  [October 1, 2010 to October 1, 2011]
------------------------------------------------------------------------
                                             NDA/ANDA
                                            (percent of    BLA (percent
                                              total)       of total) \1\
------------------------------------------------------------------------
Concluded PMRs:
    Requirement met (fulfilled).........        55 (70%)        16 (84%)
    Requirement not met (released and           21 (27%)          0 (0%)
     new revised requirement issued)....
    Requirement no longer feasible or             3 (4%)         3 (16%)
     product withdrawn (released).......
                                         -------------------------------
        Total...........................              79              19
Concluded PMCs:
    Commitment met (fulfilled)..........       109 (85%)        44 (80%)
    Commitment not met (released and new         12 (9%)          2 (4%)
     revised requirement/commitment
     issued)............................
    Commitment no longer feasible or              7 (5%)         9 (16%)
     product withdrawn (released).......
                                         -------------------------------
        Total...........................             128              55
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.


    Dated: February 28, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
 [FR Doc. 2012-5302 Filed 3-5-12; 8:45 am]
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